Understanding Interpretation of First Trimester Screening Results

Based on the very large number of comments and questions I continue to receive related to the interpretation of the results of ‘combined first trimester screening for aneuploidy’, it is clear that there is a lot of confusion among both patients and providers alike regarding the meaning of the results and the contributions of the individual values to the actual ‘risk assessment’. My response to the two queries below may help to answer some of the questions readers may have related to this very valuable screening test…• At Thu Apr 10, 05:39:00 AM 2008, Anonymous said…I am 40 years old, 11 weeks pregnant by ICSI (intracytoplasmic sperm injection) and very worried. Can you please help me to understand these results (MoM?) taken 10+3 week.

PAPP-A: 1169,58 mU/Lfree beta hCG: 47,40 Mg/lNT: 2.5

The risk for Down syndrome was estimated to be 1 in 10.

Thank you!•

At Mon Apr 14, 06:02:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…To anonymous Apr 10: In your case, the increased risk for Down syndrome is probably being driven by at least your age and the relatively increased NT (nuchal translucency) measurements. I cannot comment on the absolute values of the PAPP-A and hCG because I need the multiples of the median (MoM) for these to see how they might be contributing to the overall risk. Let me explain...

Maternal serum markers (in this case the free beta-hCG and the PAPP-A) steadily change as the pregnancy progresses (i.e., by weeks' gestation) and these changes are quite significant during this early part of the pregnancy while the placental tissues are rapidly proliferating. During pregnancies in which the baby is chromosomally normal, the hCG levels begin to drop toward the end of first trimester and then level off and the PAPP-A levels tend to increase gradually throughout the pregnancy. In the case of a baby with Down syndrome (trisomy 21), the hCG levels are often elevated and the difference between chromosomally normal babies and those with Down syndrome increase as the pregnancy progresses. Earlier in pregnancy, PAPP-A levels tend to be lower than normal in Down syndrome, but the difference between chromosomally normal babies and Down’s babies tends to decrease with gestational age. In the case of trisomy 18 (Edwards’ syndrome), both hCG and PAPP-A levels tend to be lower than normal.

Because of the changes in serum marker levels by gestational age, for accurate interpretation of the test results, a different reference range must be used for each week of gestation, depending on when the test is drawn. To avoid the multiple reference range problems and also to standardize test results between different laboratories, whose reference ranges also vary, a MEDIAN value for test results in normal pregnancies is determined in each laboratory for each week of gestation.

If one arranges all the numbers in a set of data from the highest to the lowest values, the ‘median’ is the number in the middle of the data set. It is not the ‘average’ or ‘mean’ of the dataset. The median is primarily used for skewed distributions and it is seen as a better indication of central tendency than the arithmetic mean. It specifiaclly helps to provide a more robust measure of ‘central tendency' in datasets that contain outlier values. For example, if you have a dataset that contains the 9 numbers (2, 2, 2, 3, 3, 3, 4, 5, 21), the median would be 3 (the fifth number, but the arithmetic mean would be 5.

Anyway, a patient's maternal serum marker results are then expressed in each laboratory as multiples of the median (MoM), rather than as a raw 'marker' concentration. It has been found that maternal weight, maternal race/ethnicity, smoking, and maternal diabetes mellitus (insulin-dependent) variably affect maternal serum marker value. Most laboratories today correct the MoM for these conditions so that a given MoM value accurately reflects the risk of abnormality. Laboratories request that information related to these conditions be included, along with the gestational age, when the specimen is submitted. There is sufficient data available now that these 'corrections' improve the reliability of the screening tests. All this is done by computer analysis of very large data bases, so I am not able to push the numbers with my own little brain!

Thanks for a good question and I hope this helps you understand your test results better. Dr T

• At Mon Mar 31, 08:39:00 AM 2008, Anonymous said…

Dr. Trofatter,

This posting is timely as I have just received back my results of the first trimester risk assessment and was found to be ‘screen positive’ with a risk of 1 in 33 for Down's. My baby’s nuchal translucency was 1.7mm, there was a nasal bone present, my free beta-hCG was 2.43 MoM, and the PAPP-A was 0.48 MoM. I'm trying (unsuccessfully) to focus on the 97% chance that my baby is fine. I elected not to have CVS because I received my results too close to the end of the 12th week to have sufficient time to decide, so I've deferred to having an amniocentesis in 3 weeks. My question is why 32 of the 33 women will have a normal child but still have abnormal lab values? Also, can more credence be given to the blood tests or the ultrasound in having predictive value or do all receive equal weight in determining risk?Thank you for your time. I enjoy your blog very much.

• At Fri Apr 04, 07:37:00 AM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…To anonymous Mar 31: The different variables (maternal age, hCG, PAPP-A, nuchal translucency, etc) are given variable weights when factored into the risk assessment and that evens varies with gestational age (as detailed in the response above). I do not know exactly how that is determined and rely entirely on the large database that we all use when we perform these studies. The reason more 'screen positive' women will actually have a "normal" baby is one of the primary downsides of a SCREENING test rather than a diagnostic test. Screening tests are valuable if they have low false negative results (in other words, they point to the possibility of an abnormality), but the trade-off is a comparatively high false positive rate.

In the case of first trimester screening, if you are "screen positive (abnormal)" it is unlikely that a baby with trisomies 21 or 18/13 will be missed and that gives you the opportunity to have a diagnostic study done that will actually rule in or rule out the abnormality. In contrast to popular opinion, good screening tests do help reduce the number of diagnostic procedures that have to be done and help to pick up abnormalities in patients who would not ordinarily be considered 'high risk' by age alone, for example, in the case of fetal chromosomal abnormalities.

Hope this helps. Best of luck to you and let us know how things turn out! Dr T

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